Adherence to guidelines forcreatinine and potassium monitoringand discontinuation followingrenin–angiotensin system blockade:a UK general practice-basedcohort study

Morten Schmidt,1,2,3 Kathryn E Mansfield,1 Krishnan Bhaskaran,1 Dorothea Nitsch,1

Henrik Toft Sørensen,2 Liam Smeeth,1 Laurie A Tomlinson1

To cite: Schmidt M,Mansfield KE, Bhaskaran K,et al. Adherence to guidelinesfor creatinine and potassiummonitoringand discontinuation followingrenin–angiotensin systemblockade: a UK generalpractice-based cohort study.BMJ Open 2017;7:e012818.doi:10.1136/bmjopen-2016-012818

▸ Prepublication history andadditional material isavailable. To view please visitthe journal (http://dx.doi.org/10.1136/bmjopen-2016-012818).

Received 27 May 2016Revised 5 August 2016Accepted 12 October 2016

For numbered affiliations seeend of article.

Correspondence toDr Morten Schmidt;morten.schmidt@clin.au.dk

ABSTRACTObjectives: To examine adherence to serumcreatinine and potassium monitoring anddiscontinuation guidelines following initiation oftreatment with ACE inhibitors (ACEI) or angiotensinreceptor blockers (ARBs); and whether high-riskpatients are monitored.Design: A general practice-based cohort study usingelectronic health records from the UK Clinical PracticeResearch Datalink and Hospital Episode Statistics.Setting: UK primary care, 2004–2014.Subjects: 223 814 new ACEI/ARB users.Main outcome measures: Proportion of patientswith renal function monitoring before and after ACEI/ARB initiation; creatinine increase ≥30% or potassiumlevels >6 mmol/L at first follow-up monitoring; andtreatment discontinuation after such changes. Usinglogistic regression models, we also examined patientcharacteristics associated with these biochemicalchanges, and with follow-up monitoring within theguideline recommendation of 2 weeks after treatmentinitiation.Results: 10% of patients had neither baseline norfollow-up monitoring of creatinine within 12 monthsbefore and 2 months after initiation of an ACEI/ARB,28% had monitoring only at baseline, 15% only atfollow-up, and 47% both at baseline and follow-up.The median period between the most recent baselinemonitoring and drug initiation was 40 days (IQR12–125 days). 34% of patients had baseline creatininemonitoring within 1 month before initiating therapy,but <10% also had the guideline-recommended follow-up test recorded within 2 weeks. Among patientsexperiencing a creatinine increase ≥30% (n=567,1.2%) or potassium level >6 mmol/L (n=191, 0.4%),80% continued treatment. Although patients with priormyocardial infarction, hypertension or baselinepotassium >5 mmol/L were at high risk of ≥30%increase in creatinine after ACEI/ARB initiation, therewas no evidence that they were more frequentlymonitored.

Conclusions: Only one-tenth of patients initiatingACEI/ARB therapy receive the guideline-recommendedcreatinine monitoring. Moreover, the vast majority ofthe patients fulfilling postinitiation discontinuationcriteria for creatinine and potassium increases continueon treatment.

INTRODUCTIONRenin angiotensin system blockade usingACE inhibitors (ACEI) and angiotensinreceptor blockers (ARBs) is a mainstay intreatment of hypertension,1 heart failure,2

diabetic microalbuminuria or proteinuric

Strengths and limitations of this study

▪ This is the largest monitoring study until now,examining both adherence to creatinine andpotassium monitoring and discontinuationguidelines following initiation of ACE inhibitorsor angiotensin receptor blockers in UK primarycare, and whether patients are monitored inaccordance with their individual risk profile.

▪ Use of the UK Clinical Practice Research Datalinkand Hospital Episode Statistics ensured that thestudy was population-based and not restricted tospecific demographic, hospital or insurancegroups.

▪ Blood tests performed in hospital systems werenot recorded in the Clinical Practice ResearchDatalink, but the results were consistent forpatients with no recent hospital admissions.

▪ If the recording of creatinine levels was notmissing completely at random, the associationsbetween patient characteristics and creatinineincrease may have been underestimated.

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renal diseases,3 and after myocardial infarction.4

However, some patients experience a sudden decline inkidney function when initiating these drugs, presumablydue to antagonism of the angiotensin II-mediated effer-ent arteriolar constriction or impaired kidney excretionof potassium.5 6

The potential impact on kidney function should beevaluated by comparing preinitiation and postinitiationlevels of serum creatinine and potassium.7

Discontinuation is recommended if the rise in creatinineexceeds 30% above baseline or if hyperkalaemiadevelops.8 It is unclear whether these recommendationsare routinely followed in clinical practice.9

A few studies have compared baseline and follow-upmonitoring results,9 but large studies using contempor-ary data with reference to current guidelines are lacking,and it is unknown whether patients’ individual risk ofrenal impairment influences their likelihood of beingmonitored.9 We therefore examined adherence to cre-atinine and potassium monitoring and treatment discon-tinuation guidelines following ACEI/ARB initiation inUK primary care, and whether patients are monitored inaccordance with their individual risk profile.

METHODSData sourcesWe used the UK’s Clinical Practice Research Datalink(CPRD) linked to hospital record data from theHospital Episode Statistics (HES) database. The CPRDdatabase contains primary care electronic health recorddata from 7% of the UK population (∼15 millionpatient lives, with ∼8 million currently underfollow-up).10 Patients included in the CPRD are largelyrepresentative of the UK population in terms of age, sexand ethnicity.10 11 Information recorded in the databaseincludes demographics such as sex and year of birth, thelocation of the general practice, medical diagnoses(based on ‘Read’ codes), drug prescriptions and a rangeof routine laboratory test results. HES records cover allhospital admissions for patients covered by the NationalHealth Service (NHS) who receive treatment eitherfrom English NHS trusts or independent providers.10 11

Fifty-eight per cent of general practices included in theCPRD have agreed to HES linkage.10 We obtainedlinked data on socioeconomic status (index of multipledeprivation) based on area of residence.

Monitoring guidelinesConsistent with other international guidelines, theNational Institute for Health and Care Excellence(NICE) recommends baseline testing of creatinine wheninitiating ACEI/ARB therapy in patients with hyperten-sion,1 heart failure,2 myocardial infarction4 or chronickidney disease (CKD).3 The time interval for baselinetesting is not further specified.1–4 Among patients withheart failure, myocardial infarction and CKD, NICErecommends follow-up monitoring within 2 weeks of

treatment initiation,2–4 and for patients with myocardialinfarction at least annually thereafter.4 A baseline assess-ment and follow-up test within 2 weeks is also recom-mended by the UK Renal Association,12 as well as thefrequently used online web resource General Practice(GP) Notebook.13 GP Notebook additionally recom-mends monitoring 1, 3, 6 and 12 months after the firstfollow-up test.13 NICE recommends not to initiateACEI/ARBs in patients with a baseline potassium level>5 mmol/L and to discontinue therapy if potassiumrises above 6 mmol/L.

ACEI/ARB initiatorsWe identified a cohort of all HES-linked CPRD patientsaged ≥18 years, who initiated ACEI/ARB treatmentbetween 1 January 2004 and 31 March 2014. We did notinclude earlier calendar periods, as laboratory databefore 2004 were incomplete due to interface problemsbetween laboratory reporting software and GP practicemanagement software.14 Also, creatinine testing wasincentivised in 2004 with the introduction of the dia-betes Quality and Outcomes Framework (QOF) andfurther in 2006 with the CKD QOF.14 To rule out anypotential influence of incomplete data around 2004, wealso examined the most recent 5-year calendar periodseparately in a sensitivity analysis. New users weredefined as persons with at least 1 year of continuousregistration in the CPRD before their first recordedACEI/ARB prescription.

Laboratory dataAll creatinine test results were extracted from thegeneral practice records of the study population, usingcreatinine-specific codes in CPRD. Cross-reference wasthen made to creatinine test results identified from abroad Read code search. Any irrelevant codes wereexcluded. Renal function testing in the UK includes cre-atinine and potassium, so it can be inferred that testingfrequency is similar to creatinine for potassium. Whenwe conducted analyses related to potassium levels, werepeated the procedure used to identify creatinine levelsfor potassium test results.

Patient characteristicsWe obtained information for all patients on age, sex, cal-endar period of ACEI/ARB initiation (2004–2008 and2010–2014), socioeconomic status (quintiles of the 2004index of multiple deprivation scores), lifestyle factors(smoking, alcohol intake and body mass index), baselinepotassium level (≤5 or >5 mmol/L), CKD, cardiovascu-lar comorbidities (heart failure, myocardial infarction,hypertension, peripheral arterial disease and arrhyth-mia) and diabetes.15 We used algorithms for smokingstatus, alcohol intake and body mass index based on themost recent records in the CPRD before ACEI/ARB ini-tiation.16 17 As measures of baseline creatinine andpotassium levels, we used the single most recent meas-urement within 12 months before the first ACEI/ARB

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prescription. We calculated the estimated glomerular fil-tration rate (eGFR) level from the most recent creatin-ine measurement and CKD stage from the CKDEpidemiology Collaboration (CKD-EPI) equation.18

Cardiovascular comorbidities and diabetes were identi-fied from both the CPRD and HES based on diagnosesrecorded prior to ACEI/ARB initiation. The code listsfor all variables are provided in the onlinesupplementary appendix.

Patient involvementThe study included no patient involvement.

Statistical analysisWe described ACEI/ARB users according to patientcharacteristics, both overall and according to creatininemonitoring status (no baseline or follow-up monitoring,baseline only, follow-up only, and both baseline andfollow-up monitoring). Baseline monitoring was definedas a test performed on the date of drug initiation orwithin either 12 months before (wide interval) or1 month before initiation (more ideal interval assumedto be driven by planned ACEI/ARB initiation). Toaccord with the postinitiation monitoring intervalrecommended from previous trial data, we consideredonly follow-up monitoring within the first 2 months afterdrug initiation.8

We calculated the proportion of persons in the totalcohort of new users who had baseline and follow-upmonitoring (within 1, 3 and 12 months before drug initi-ation and within 2 weeks, 1 month and 2 months afterinitiation). We then computed the proportion ofpersons with both baseline and initial follow-up monitor-ing within the guideline-recommended interval of2 weeks following drug initiation.We repeated the analyses for continuing users, in

order to examine adherence to the stricter guidelinerecommendations for ongoing monitoring (ie, monitor-ing within 1, 3, 6 and 12 months after the first retest).13

Continuation was defined as ACEI/ARB use beyond30 days following the monitoring date, that is, when theend date of the first continuous course of therapy wasafter the date of the first monitoring date plus 30 days(to allow for stockpiling). The end date of each pre-scription was calculated by adding the prescription dur-ation (total number of tablets prescribed divided by thespecified number of tablets per day) to the prescriptiondate. In identifying continuous courses of therapy, weallowed for a 30-day gap between the end date of oneprescription and the start of the next consecutiveprescription.In sensitivity analyses, we repeated the analyses (1)

extending the follow-up window for the first follow-upmonitoring from 2 to 3 weeks to account for minordelays; (2) including only the most recent calendarperiod (2009–2014) to account for temporal changes indata completeness and quality of care; (3) excludingpatients with a hospital admission or discharge date

within 1 month before or after their first ACEI/ARB pre-scription, in order to account for drug initiation and anysubsequent renal function tests occurring in the hospitaland therefore not captured in the CPRD; (4) focusingon specific patient subgroups (heart failure, myocardialinfarction, hypertension, CKD (eGFR<60 mL/min/1.73 m2), peripheral arterial disease and diabetes); and(5) defining drug use continuation as ACEI/ARB usebeyond 90 days (instead of 30 days) after the first retestdate.We used the subcohort of patients with both baseline

and follow-up monitoring to calculate the proportion ofpatients with creatinine increases ≥30% or potassiumlevels >6 mmol/L at the first follow-up monitoringwithin 2 months after initiation, as well as the proportionof patients continuing treatment despite these contrain-dications for use.Finally, we fitted a logistic regression model to identify

patient characteristics associated with a severe decline inrenal function (creatinine increase ≥30% or potassiumlevel >6 mmol/L) and compared these characteristicswith those associated with receiving postinitiationfollow-up monitoring within 2 weeks. The modelincluded age, sex, CKD stage, cardiovascular comorbid-ities, diabetes and baseline potassium level (>5 vs≤5 mmol/L). In three additional model-based sensitivityanalyses, we repeated the analyses (1) excluding patientswith a recent hospitalisation (as defined above); (2)omitting baseline potassium from the model to examinethe extent of potential overfitting when both baselinepotassium and CKD stage were kept in the model; and(3) also adjusting additionally for ethnicity.All analyses were performed using the STATA 14 statis-

tical software package.

RESULTSSerum creatinine monitoring before and afterACEI/ARB initiationWe identified 223 814 new users of ACEI/ARB. We com-pared these patients in four groups: 21 411 (10%) hadno baseline or follow-up creatinine tests within12 months before and 2 months after treatment initi-ation, 63 359 (28%) had only a baseline test, 33 185(15%) had only follow-up tests, and 105 859 (47%) hadboth baseline and follow-up tests (table 1). Median agevaried only slightly between the groups (60, 62, 59 and63 years, respectively) and there were no substantial dif-ferences in socioeconomic status, lifestyle factors or per-ipheral arterial disease. Compared with patients withneither preinitiation nor postinitiation monitoring,patients with both were more likely to have diagnosedhypertension (76% vs 61%) and diabetes (20% vs 7%),but less likely to have diagnosed heart failure (4% vs7%), myocardial infarction (4% vs 18%) and arrhythmia(7% vs 10%). Among patients with baseline monitoring,83% did not have CKD, 13% stage 3a, 3% stage 3b,0.5% stage 4 CKD. In the same population, 7% started

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ACEI/ARB therapy despite baseline potassium above5 mmol/L. The median number of days between base-line monitoring and first prescription date was 40 days(IQR 12–125 days).

Among all patients initiating ACEI/ARB therapy, theproportion of patients receiving creatinine testing beforeinitiation was 76% within 12 months of treatment initi-ation, declining to 34% within 1 month before initiation

Table 1 Characteristics of patients initiating ACE inhibitors or ARBs in the UK primary care during 2004–2014, by monitoring

groups

Serum creatinine monitoring*

Total

No baseline or

follow-up tests

Baseline test

only

Follow-up test

only

Baseline and

follow-up tests

Total number 21 411 (100) 63 359 (100) 33 185 (100) 105 859 (100) 223 814 (100)

Female sex 8882 (41) 27 722 (44) 14 570 (44) 49 109 (46) 100 283 (45)

Age (years)

<50 5019 (23) 13 697 (22) 8732 (26) 19 910 (19) 47 358 (21)

50–59 5485 (26) 15 135 (24) 9115 (27) 24 866 (23) 54 601 (24)

60–69 4863 (23) 15 586 (25) 7776 (23) 27 790 (26) 56 015 (25)

70–79 3579 (17) 12 193 (19) 5066 (15) 22 152 (21) 42 990 (19)

80+ 2465 (12) 6748 (11) 2496 (8) 11 141 (11) 22 850 (10)

Calendar period

2004–2008 14 814 (69) 40 667 (64) 19 808 (60) 60 902 (58) 136 191 (61)

2009–2014 6597 (31) 22 692 (36) 13 377 (40) 44 957 (42) 87 623 (39)

SES quintiles

1 (low) 5153 (24) 15 290 (24) 8533 (26) 25 577 (24) 54 553 (24)

2 4725 (22) 14 331 (23) 7887 (24) 24 851 (23) 51 794 (23)

3 4341 (20) 13 028 (21) 6890 (21) 22 629 (21) 46 888 (21)

4 4254 (20) 12 140 (19) 5931 (18) 19 318 (18) 41 643 (19)

5 (high) 2925 (14) 8508 (13) 3898 (12) 13 359 (13) 28 690 (13)

Missing 13 (0) 62 (0) 46 (0) 125 (0) 246 (0)

Smoking status

Never 7860 (37) 22 496 (36) 12 229 (37) 36 895 (35) 79 480 (36)

Ever 13 433 (63) 40 797 (64) 20 915 (63) 68 939 (65) 144 084 (64)

Missing 118 (1) 66 (0) 41 (0) 25 (0) 250 (0)

Alcohol intake

No use 2556 (12) 7819 (12) 3409 (10) 11 088 (10) 24 872 (11)

Current 15 495 (72) 47 322 (75) 25 656 (77) 82 870 (78) 171 343 (77)

Former 1328 (6) 4499 (7) 1933 (6) 7490 (7) 15 250 (7)

Missing 2032 (9) 3719 (6) 2187 (7) 4411 (4) 12 349 (6)

BMI groups

Underweight 282 (1) 700 (1) 304 (1) 1008 (1) 2294 (1)

Healthy weight 5666 (26) 15 406 (24) 8089 (24) 24 972 (24) 54 133 (24)

Overweight 7677 (36) 23 755 (37) 12 484 (38) 40 556 (38) 84 472 (38)

Obesity 6009 (28) 20 660 (33) 10 527 (32) 35 887 (34) 73 083 (33)

Missing 1777 (8) 2838 (4) 1781 (5) 3436 (3) 9832 (4)

CKD (eGFR)†

Stage ≤2 (≥60) 10 326 (48) 53 773 (85) 19 470 (59) 87 484 (83) 171 053 (76)

Stage 3a (45–59) 1137 (5) 7382 (12) 1766 (5) 13 913 (13) 24 198 (11)

Stage 3b (30–44) 217 (1) 1885 (3) 265 (1) 3854 (4) 6221 (3)

Stage 4 (15–29) 24 (0) 319 (1) 29 (0) 608 (1) 980 (0)

Not measured 9707 (45) 0 (0) 11 655 (35) 0 (0) 21 362 (10)

CV comorbidities‡

Heart failure 1568 (7) 3270 (5) 1386 (4) 4583 (4) 10 807 (5)

Myocardial infarction 3881 (18) 4653 (7) 3203 (10) 4620 (4) 16 357 (7)

Hypertension 13 023 (61) 44 273 (70) 24 195 (73) 80 946 (76) 162 437 (73)

Peripheral arterial disease 471 (2) 1590 (3) 523 (2) 2547 (2) 5131 (2)

Arrhythmia 2057 (10) 4973 (8) 2000 (6) 7123 (7) 16 153 (7)

Diabetes mellitus 1399 (7) 13 586 (21) 1992 (6) 21 548 (20) 38 525 (17)

*Monitoring groups based on baseline (within 12 months before) and follow-up (within 2 months after) serum creatinine monitoring.†Calculated from most recent creatinine measurement within 12 months before the first prescription date.‡Diagnosis ever registered before ACE/ARB initiation in CRPD or HES.ARB, angiotensin receptor blocker; BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerularfiltration rate; HES, Hospital Episode Statistics; SES, socioeconomic status.

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(table 2). The proportion with follow-up testing aftertreatment initiation was 29% within 2 weeks, increasingto 62% within 2 months. Among ACEI/ARB initiatorswho had a baseline test within 12 months, 21% also had afollow-up test within 2 weeks after starting treatment(table 3). However, among patients undergoing testingwithin 1 month prior to treatment initiation, only 9%had also the recommended follow-up test within 2 weeksof treatment start. When we extended the follow-upwindow to 3 weeks, this proportion increased to only 14%(table 3). Among patients continuing treatment, only 1%had follow-up measurements at 1, 3, 6 and 12 monthsafter the first retest, in compliance with the strictest rec-ommendation (eTable 1). These results were unchangedwhen the analysis was restricted to the most recent

calendar period (eTables 1–2) and to patients with heartfailure, myocardial infarction, hypertension, peripheralarterial disease, diabetes or no recent hospitalisation(eTable 3). Only patients with CKD received a slightlyhigher degree of monitoring (13%) within 2 weeks fol-lowing treatment initiation (eTable 3). The proportionwith follow-up testing after treatment initiation was alsounchanged when results were stratified by date of ACEI/ARB initiation in 2-year intervals (eTable 4).

Serum creatinine and potassium changes afterACEI/ARB initiationAmong patients receiving the recommended renal func-tion monitoring, 567 (1.2%) experienced a creatinineincrease ≥30% and 191 (0.4%) a potassium level>6 mmol/L at their first follow-up test within 2 monthsof treatment initiation (1.4% experienced the increasein creatinine and/or potassium) (table 4). Among thesepatients, 80% continued treatment beyond 30 days fol-lowing the monitoring date (table 4). The sensitivity ana-lysis showed that 65% of patients with a creatinineincrease ≥30% and 60% of those with a potassium level>6 mmol/L also continued treatment beyond 90 daysafter the monitoring date (eTable 5). The resultsremained consistent for longer baseline monitoringintervals (eTable 5).

Patients at high risk for creatinine increases ≥30%When we examined patient characteristics associatedwith a creatinine increase ≥30% and adjusted for the

Table 2 Prevalence of baseline and follow-up serum

creatinine monitoring among patients initiating ACE

inhibitors or angiotensin receptor blockers, 2004–2014

Serum creatinine, ≥1 test

Total number n=223 814 (100%)

Baseline testing

≤12 months before 169 218 (76%)

≤3 months before 115 348 (52%)

≤1 month before 75 476 (34%)

Follow-up testing

≤2 weeks after 65 090 (29%)

≤1 month after 114 244 (51%)

≤2 months after 139 044 (62%)

Table 3 Prevalence of baseline and follow-up serum creatinine monitoring among patients initiating ACE inhibitors or

angiotensin receptor blockers according to clinical guideline recommendations

Clinical guidelines

All initiators

n=223 814 (100%)

NICE

heart failure

NICE

MI

NICE/UKRA

hypertension

NICE

CKD

GP

Notebook

Wide baseline

interval

(≤12-months)

Ideal baseline

interval

(≤1 month)

Baseline testing x x x x x 169 218 (76%) 75 476 (34%)

+Follow-up test ≤2 weeks* x NA x x x 46 486 (21%) 19 679 (9%)

+Follow-up test ≤3 weeks† 70 792 (32%) 30 451 (14%)

*Follow-up test among those with baseline measurements.†Sensitivity analysis illustrating the importance of 2-week vs 3-week cut-off interval in follow-up test intervals.CKD, chronic kidney disease; GP, general practice; MI, myocardial infarction; NA, not applicable; NICE, National Institute for Health and CareExcellence; UKRA, United Kingdom Renal Association.

Table 4 Proportion of new users of ACE inhibitors or angiotensin receptor blockers who continue or discontinue treatment

according to guideline recommended cut-off levels of serum creatinine and potassium at follow-up testing*

Continuation† Discontinuation† Total

Total number, % 42 942 (93.1) 3178 (6.9) 46 120 (100)

Serum creatinine increase ≥30%, n (%) 462 (81.5) 105 (18.5) 567 (100)

Serum potassium >6 mmol/L, n (%) 150 (78.5) 41 (21.5) 191 (100)

*Calculated from the most recent measurements within 1 month before and 2 months after drug initiation.†A patient was considered a continuous user when the end date of the first continuous course of therapy was larger than the date of the firstfollow-up monitoring +30 days (to allow for stockpiling and irregular use).

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Table 5 Association between patient characteristics and serum creatinine increase ≥30% and follow-up monitoring within 2 weeks following initiation of ACE inhibitors or

angiotensin receptor blockers

OR (95% CIs)

Characteristics

Serum creatinine monitoring ≤2 weeks Serum creatinine increase ≥30%* Serum potassium increase ≥30%*

Age-adjusted and

sex-adjusted Fully adjusted†

Age-adjusted and

sex-adjusted Fully adjusted†

Age-adjusted and

sex-adjusted Fully adjusted†

Female sex 1.07 (1.04 to 1.10) 1.07 (1.04 to 1.09) 1.39 (1.26 to 1.53) 1.63 (1.47 to 1.80) 0.87 (0.66 to 1.16) 0.94 (0.70 to 1.26)

Age (years)

<50 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)

50–59 0.98 (0.94 to 1.01) 0.98 (0.95 to 1.02) 0.88 (0.74 to 1.05) 0.86 (0.72 to 1.03) 1.29 (0.79 to 2.11) 1.10 (0.67 to 1.81)

60–69 1.05 (1.02 to 1.09) 1.05 (1.01 to 1.09) 1.03 (0.88 to 1.21) 1.00 (0.85 to 1.19) 1.35 (0.84 to 2.17) 0.97 (0.60 to 1.58)

70–79 1.18 (1.14 to 1.23) 1.18 (1.13 to 1.23) 1.49 (1.27 to 1.74) 1.36 (1.15 to 1.61) 1.65 (1.02 to 2.66) 0.74 (0.43 to 1.26)

80+ 1.20 (1.14 to 1.25) 1.17 (1.11 to 1.23) 2.72 (2.32 to 3.20) 2.02 (1.68 to 2.44) 2.75 (1.67 to 4.53) 0.73 (0.41 to 1.32)

CKD stage

No CKD (≥60) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)

Stage 3a (45–59) 1.00 (0.96 to 1.04) 1.00 (0.96 to 1.04) 0.62 (0.53 to 0.73) 0.60 (0.51 to 0.70) 2.48 (1.66 to 3.71) 2.06 (1.36 to 3.11)

Stage 3b (30–44) 0.99 (0.93 to 1.06) 1.01 (0.94 to 1.08) 1.01 (0.82 to 1.24) 0.88 (0.71 to 1.09) 7.51 (4.75 to 11.9) 5.10 (3.16 to 8.22)

Stage 4 (15–29) 1.42 (1.21 to 1.67) 1.41 (1.20 to 1.66) 2.16 (1.52 to 3.05) 1.72 (1.18 to 2.51) 24.0 (13.5 to 42.6) 11.4 (6.07 to 21.4)

Comorbidities*

Heart failure 1.15 (1.09 to 1.23) 1.16 (1.08 to 1.23) 4.00 (3.49 to 4.58) 2.93 (2.51 to 3.42) 2.90 (1.90 to 4.42) 2.22 (1.38 to 3.58)

MI 0.80 (0.75 to 0.85) 0.77 (0.72 to 0.82) 2.33 (1.98 to 2.74) 1.57 (1.32 to 1.87) 2.12 (1.33 to 3.39) 1.35 (0.80 to 2.25)

Hypertension 1.00 (0.97 to 1.02) 1.05 (1.00 to 1.11) 0.62 (0.56 to 0.68) 1.58 (1.36 to 1.84) 0.60 (0.45 to 0.80) 1.02 (0.63 to 1.65)

PAD 1.09 (1.01 to 1.18) 1.11 (1.02 to 1.20) 2.10 (1.70 to 2.60) 1.87 (1.50 to 2.33) 2.14 (1.18 to 3.86) 1.53 (0.82 to 2.88)

Arrhythmia 1.09 (1.03 to 1.14) 0.98 (0.95 to 1.01) 2.37 (2.07 to 2.71) 0.77 (0.69 to 0.86) 1.41 (0.90 to 2.21) 0.77 (0.56 to 1.05)

Diabetes mellitus 0.93 (0.90 to 0.96) 0.93 (0.90 to 0.96) 1.09 (0.97 to 1.22) 1.04 (0.92 to 1.18) 0.97 (0.69 to 1.36) 0.90 (0.63 to 1.29)

Baseline K>5 mmol/L 1.04 (1.00 to 1.10) 1.04 (0.99 to 1.09) 1.04 (0.86 to 1.25) 0.97 (0.80 to 1.17) 8.22 (6.14 to 11.0) 6.68 (4.94 to 9.02)

*The increase was based on the difference between the most recent baseline measurements within 12 months before and first follow-up measurement within 2 months after drug initiation. Allanalyses were restricted to those with both baseline and follow-up measurements (n=105 859).†Adjusted for sex, age, CKD, heart failure, MI, hypertension, PAD, arrhythmia, diabetes and calendar period of prescription start.CKD, chronic kidney disease; K, potassium; MI, myocardial infarction; PAD, peripheral arterial disease.

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other characteristics in a multivariable analysis (table 5),we found an increased OR for women (1.6-foldincreased), for age above 70 years (at least 1.3-foldincreased), for CKD stage 4 (1.6-fold increased), heartfailure (2.9-fold increased), peripheral arterial disease(1.9-fold increased), myocardial infarction (1.6-foldincreased) and hypertension (1.6-fold increased).

Patients at high risk for potassium >6 mmol/LBaseline potassium level and CKD stage, but not ageand sex, were associated with potassium levels >6 mmol/L after ACEI/ARB initiation. Thus, the OR was seven-fold increased for baseline potassium >5 mmol/L,twofold increased for CKD stage 3a, fivefold increasedfor stage 3b, and 11-fold increased for stage 4 (table 5).Among cardiovascular comorbidities, heart failure wasassociated with the strongest OR of a potassium level>6 mmol/L (2.22, 95% CI 1.38 to 3.58).

Monitoring high-risk patientsSome characteristics associated with increased odds ofhaving ≥30% rise in creatinine were also associated witha greater likelihood of having a follow-up test within2 weeks following drug initiation. These included olderage: persons aged 70 years or above compared with≤50 years (1.18, 95% CI 1.13 to 1.23 for 70–79 years and1.17, 95% CI 1.11 to 1.23 for 80+ years), CKD stage 4compared with no CKD (1.41, 95% CI 1.20 to 1.66),heart failure (1.16, 95% CI 1.08 to 1.23) and peripheralarterial disease (1.11, 95% CI 1.02 to 1.20). However,other characteristics associated with increased odds ofhaving ≥30% rise in creatinine were not associated witha greater likelihood of having a follow-up test within2 weeks following drug initiation: there was no substan-tially increased OR (>10%) associated with female sex(1.07, 95% CI 1.04 to 1.09), prior history of myocardialinfarction (0.77, 95% CI 0.72 to 0.82), hypertension(1.05, 95% CI 1.00 to 1.11) or baseline potassium>5 mmol/L (1.04, 95% CI 0.99 to 1.09). When weexcluded patients with a recent hospital admission, thereduced OR for myocardial infarction was no longerobserved (0.93, 95% CI 0.80 to 1.08) (eTable 6). Finally,the results remained consistent when we omitted adjust-ment for baseline potassium (data not shown) and whenwe adjusted additionally for ethnicity (eTable 6).

DISCUSSIONOnly one-tenth of patients initiating ACEI/ARBs in UKprimary care appear to receive the guideline-recommended creatinine monitoring. One in 15 patientsstarted ACEI/ARBs despite baseline potassium above therecommended level, which was also shown to be a strongpredictor for severe postinitiation hyperkalaemia.Among monitored patients, a creatinine increase ≥30%or a potassium level >6 mmol/L occurred in almost 1.5%of patients, and most did not discontinue therapy despiteguideline recommendations to stop. Although patients

with prior myocardial infarction, hypertension or a highbaseline potassium level were at higher risk of suddendecline in kidney function after ACEI/ARB initiation,there was no evidence that these patient groups weremonitored more frequently while initiating the drugs.

Strengths and limitationsSeveral issues should be considered when interpretingour study results. Its large sample size increased preci-sion. Use of the CPRD ensured that the study wasgeneral practice-based and not restricted to specificdemographic, hospital or insurance groups.Over the time course of this study, multiple factors

have impacted on the prescribing of ACEI/ARB andmeasurement of renal function in primary care, forexample, the introduction of the relevant NICE guide-lines, and QOF reimbursement for testing in certainsubgroups. We also did not have information about clini-cal initiatives such as heart failure nurses and ACEI/ARB stopping rules (‘sick-day rules’). While our mainresults provide summary measures over a 10-year period,sensitivity analyses confirm that despite these changes,the proportion receiving the guideline suggested thatbiochemical monitoring does not vary during the studyperiod. We did not have access to blood tests performedin hospital systems, which may have been reported toGPs, but not recorded in CPRD. However, restricting theanalysis to patients with no recent hospital admissionswho were most likely to have had renal function mea-sured and acted on in secondary care had little effect onour findings. We did not examine testing during initi-ation of dual blockade with ACEI and ARB as this com-bination is now used very infrequently for patients withsevere comorbidities who are likely to be monitored insecondary care. Although some patients may also havebeen seen in outpatient specialty clinics, it is commonpractice for specialists to ask GPs to initiate new drugssuch as ACEI/ARBs, with local biochemical monitoring,limiting misclassification.Consistent with findings from other studies,19 we

found that ∼50% of all ACEI/ARB initiators were moni-tored both before and after treatment start. If GPs areretesting renal function in patients at higher risk of sub-stantial biochemical changes, we may have overestimatedthe proportion of patients with high potassium levels orcreatinine increases compared with the untested lower-risk general population.GP system software is used for issuing prescriptions,

ensuring the accuracy of prescription data. However, itcannot be inferred that all patients actually redeemedtheir prescription at the pharmacy and started medica-tion on the same day that it was prescribed.18 20

Similarly, the estimated coverage of prescriptions maynot be completely accurate due to such factors as stock-piling and irregular use. We also do not know whetherGPs contacted patients with elevated laboratory resultsto advise them to stop taking the medication prior tothe end of their prescriptions. However, 80% of patients

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who developed creatinine increase ≥30% after ACEI/ARB initiation were still issued a subsequent ACEI/ARBprescription.We aimed to detect discontinuation related closely in

time to the first follow-up monitoring and hence mostlikely resulting from an elevated creatinine or potas-sium result. We therefore defined continuation asACEI/ARB use beyond 30 days (the median prescrip-tion duration) after the monitoring date. Extendingthe definition of continuous use beyond 90 daysreduced the risk of misclassifying patients as continuingtreatment when they had in fact stopped. However,extending the duration also increased the risk of identi-fying discontinuation due to other reasons than creatin-ine/potassium increase, for example, death or cough.Diagnoses recorded in the CPRD generally have beenfound to have adequate validity for research pur-poses,21 22 particularly in the domains assessed by theQOF.23 24

In the logistic regression analysis to estimate factorsassociated with creatinine increase ≥30%, we excludedpatients without pre and post measurements (completecase analysis). If the recording of creatinine levels wasnot missing completely at random, the associationsbetween patient characteristics and creatinine increasemay have been underestimated.25 While this assumptioncould not be tested directly, examination of baselinecharacteristics revealed no major differences in age, sex,socioeconomic status, and lifestyle between patients withand without premonitoring and postmonitoring.Furthermore, the results were consistent for each indi-vidual patient group examined. Patients with no testingbefore or after treatment initiation (including those withpotentially haemolysed samples) only accounted for10% of all ACEI/ARB initiators.

Comparison with other studiesTo the best of our knowledge, this is the largest studyconducted until now on adherence to monitoring anddiscontinuation guidelines after ACEI/ARB initiation.Only one previous study19 examined monitoring accord-ing to guideline-recommended intervals (<14 days). Allothers have used longer intervals (eg, 30 days26 or 6months27 28), which make interpretations and implica-tions for clinical practice less clear. Poor adherence tomonitoring guidelines after ACEI/ARB initiation is notrestricted to the UK,19 28 29 but has also been reportedin the USA,30–32 Canada33 and the Netherlands.26 34

Owing to our sample size, we were able to show that thelack of monitoring occurred in all patient groups withan indication for ACEI/ARB therapy.A recent Dutch study, including 3353 patients initiat-

ing ACEI/ARBs between 2005 and 2011, found that19% had creatinine measured within 30 days and 66%within 1 year.26 Creatinine increases above 30% occurredin 1.6% of patients, and among these 70% did not dis-continue treatment.26 A Scottish study of 4056 patientswith type 2 diabetes, prescribed an ACEI/ARB between

2005 and 2009, found that 19% had both a baseline(within 90 days) and follow-up measurement (within2 weeks) of initiation. Within this cohort, 1.7% had botha creatinine increase of ≥30% and potassium level≥5.6 mmol/L.The magnitude of the risk of severe renal impairment,

as measured by creatinine increase in these observa-tional studies, was consistent with our findings, butsubstantially higher than reported in clinical trials(eg, 0.2% in the Ongoing Telmisartan Alone and inCombination with Ramipril Global Endpoint Trial(ONTARGET)).35 It is not clear from the literature howoften harm occurs around the time of initiation, whenthe risk of nephrotoxicity is thought to be greatest.8 Ifphysicians are to understand why follow-up monitoringwithin 2 weeks of treatment start matters, the short-termrisks need to be clarified. Until now, most studies havereported only on cumulative risk over entire courses oftreatment, such as the 1.1% 2-year risk for potassium of>6 mmol/L in the Studies of Left VentricularDysfunction (SOLVD) trials of patients with heartfailure.36 In contrast to clinical trial reviews, reporting a0.2% (3/1818) risk of potassium >6 mmol/L, we found a0.4% risk of hyperkalaemia already at the time of firstretesting after ACEI initiation.Extending the previous literature, our results support

that advanced age, advanced CKD and heart failure, butnot sex, increase the likelihood of being moni-tored.19 26 30 Consistent with some,26 30 but not all, previ-ous studies,28 we found no association for diabetes.However, these previous studies reporting an associationfor diabetes focused on monitoring within broader inter-vals (eg, 6 months),28 where patients with diabetes, irre-spective of ACEI/ARB initiation, were likely to receiveblood testing owing to the diabetes QOF programme.Determinants of increases in creatinine levels after

ACEI/ARB initiation are less well understood than forhyperkalaemia, but increasing age is a consistentlyreported factor.19 Advanced CKD and a range of cardio-vascular comorbidities (mostly associated with athero-sclerosis) were also important determinants in ourpatient cohort. Consistent with previous studies, wefound that the risk of hyperkalaemia was associated withCKD (most likely due to the impaired ability of the cor-tical collecting tubule to secrete potassium), heartfailure (most likely due to the decreased delivery ofsodium to the distal nephron), and high pretreatmentpotassium levels.6 8 19 37 We did not observe an associ-ation with diabetes or increasing age, as could havebeen expected due to diabetic nephropathy or age-dependent hyporeninaemic hypoaldosteronism.6

Clinical relevanceSeveral possible explanations exist for the divergencebetween the clinical guideline recommendations andthe observed monitoring and response patterns inclinical practice. The first is clinician non-adherence toordering tests. This may be due to inconsistent

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recommendations for timing and frequency of monitor-ing over time,6 consensus-based (rather than evidence-based) monitoring guidelines, and a lack of guidelinestailored to particular high-risk patients, such as thosewith CKD and heart failure. Although we found thatfollow-up monitoring correlated well with the risk ofrenal impairment after ACEI/ARB initiation for mostpatient groups, it was not observed for patients withmyocardial infarction or preinitiation high potassium.The second explanation may be patient non-adherence toordered tests. This is particularly salient in UK primarycare where blood samples may be taken in phlebotomyclinics that the patient has to visit rather than the GPpractice. Patients may find it burdensome to have bloodtests, and GPs have no direct economic incentives toensure that they are done. A third barrier is lack of evi-dence of the clinical importance of monitoring and its cost-effectiveness. ACEI/ARB-induced renal impairment israre in clinical trials, even among patients with multiplerisk factors for atherosclerotic renal artery stenosis.8 38

Trial results may therefore have led to a general percep-tion that the rarity of renal impairment obviates theneed for close monitoring. However, as observed in ourdata, the risks in real-world practice may be somewhathigher and non-negligible. In addition, previousresearch has shown that potassium monitoring in high-risk patients with CKD and diabetes may reduce serioushyperkalaemia-associated adverse events.39 Still, theextent to which an initial creatinine increase ≥30%translates into adverse long-term outcomes in real-worldpatients remains to be clarified in future studies.

Generalisability, implications and conclusionsThe majority of patients initiating treatment with ACEI/ARBs experience only minor changes in renal function.However, substantial increases in creatinine levels afterACEI/ARB initiation may not be as rare as previouslysuggested, reinforcing the need for adherence to clinicalguidelines for both pre-initiating and post-initiatingmonitoring. Moreover, the postinitiation creatinineincrease and potassium levels used in this study arewidely recognised cut-off levels, making the results inter-nationally applicable. The comparison with the previousliterature also confirms that the lack of systematic moni-toring is not exclusive to the UK. Of particular concernwas that even when appropriate monitoring was per-formed, severe renal impairment only rarely led to treat-ment discontinuation. Individual patient counsellingmay also be helpful to ensure that those at highest riskare closely monitored. More work is needed to deter-mine the prognostic importance of the changes in renalfunction that we have observed.

Author affiliations1Department of Non-Communicable Disease Epidemiology, London School ofHygiene and Tropical Medicine, London, UK2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus,Denmark3Department of Internal Medicine, Regional Hospital of Randers, Denmark

Twitter Follow Kathryn Mansfield @AnimaSophia

Contributors LAT conceived the study idea and acquired data permissions.MS, KEM and LAT designed the study. MS and KEM performed datamanagement and established the cohort. MS, KEM and LAT reviewed theliterature. The analyses were carried out by MS. All authors participated in thediscussion and interpretation of the results. MS organised the writing andwrote the initial drafts. All authors critically revised the manuscript forintellectual content and approved the final version. MS is the guarantor.

Funding MS was supported by the A.P. Møller Foundation for theAdvancement of Medical Science, Snedkermester Sophus Jacobsen & HustruAstrid Jacobsens Fond, and Christian og Ottilia Brorsons Rejselegat for yngrevidenskabsmænd og–kvinder. HTS was supported by the Program for ClinicalResearch Infrastructure (PROCRIN) established by the Lundbeck Foundationand the Novo Nordisk Foundation. KB holds a Sir Henry Dale Fellowshipjointly funded by the Wellcome Trust and the Royal Society (grant number107731/Z/15/Z). LAT and KEM are funded by a Wellcome Trust intermediateclinical fellowship to LAT (101143/Z/13/Z).

Disclaimer None of these funding sources had a role in the design, conduct,analysis or reporting of the study.

Competing interests None declared.

Ethics approval London School of Hygiene and Tropical Medicine EthicsCommittee (Approval number 6536) and the Independent Scientific AdvisoryCommittee (ISAC) for Medicines and Healthcare Products Regulatory Agency(Approval number 16_025).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance withthe terms of the Creative Commons Attribution (CC BY 4.0) license, whichpermits others to distribute, remix, adapt and build upon this work, forcommercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Correction: Adherence to guidelines for creatinine and potassium monitoring and discontinuation following renin–angiotensin system blockade: a UK general practice-based cohort study

Schmidt M, Mansfield KE, Bhaskaran K, et al. Adherence to guidelines for creatinine and potassium monitoring and discontinuation following renin–angiotensin system blockade: a UK general practice-based cohort study. BMJ Open 2017;7:e012818. doi: 10.1136/bmjopen-2016-012818

In the 3rd column of Table 5 the heading ‘Serum potassium increase ≥30%*’ should read ‘Serum potassium increase >6 mmol/L’.

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© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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